Cardiac surgery requiring cardiopulmonary bypass perfusion elicits powerful inflammatory and tissue injurious responses. As a consequence, significant distant organ damage - such as acute kidney injury - occurs, and is the principal cause of the considerable morbidity and mortality associated with these procedures. Currently, suitable concepts on the origins of the tissue injurious stimuli in this setting are lacking. This constitutes a major obstacle to the development of effective organ protection strategies. Based on provocative preliminary data, we propose a novel role for activated platelets as important inflammatory regulators through activation of perivascular mast cells at the microvascular/tissue interface. In the proposed studies, we will define the mechanisms of this interaction and its implications for end-organ injury in cardiac surgery. Our aims are: (1) Investigate the role of platelet/mast cell interactions in tissue injurious and inflammatory responses. Using rodent models of ischemia/reperfusion injury and of cardiopulmonary bypass, we will study the nature and functional relevance of platelet/mast cell interactions to early inflammatory responses and tissue injury. (2) Identify the mast cell-activating platelet factor(s) and establish their pathophysiologic relevance. Preliminary experiments based on platelet secretome analysis indicate a role of platelet-CXCL4 in mast cell activation. We will define the molecular foundations of this pathway and its impact in relevant animal models. (3) Determine the relevance of the platelet and mast cell activation to end-organ injury in cardiac surgery patients. We will investigate the link between mast cell and platelet activation and markers of inflammation and end-organ injury using our large sample repository and prospectively collected patient samples. In summary, we propose to define, for the first time, platelet/mast cell interactions as a potentially decisive mechanism of inflammatory propagation and comprehensively develop its clinical implications for improvement of organ protection strategies in cardiac surgical patients. A team of experts in the fields of mast cell (Abraham), and platelet (Bergmeier) physiology, animal models of cardiopulmonary bypass (Qing) and clinical statistics and epidemiology (Kertai) provide strong support for successful completion.